1. Field of the Invention
This invention relates to a method for greatly accelerating the rate of delivery of folic acid, and derivatives thereof, to the central nervous system by administration via the nasal route to provide extremely rapid response in the prevention or treatment of Alzheimer""s disease or stroke in a patient in need of such prevention or treatment. This method also provides for direct absorption of folic acid into the central nervous system, bypassing the metabolic enzymes circulating in the bloodstream that would otherwise destroy folic acid administered by another route.
2. Description of the Related Art
Alzheimer""s Disease
Alzheimer""s Disease (AD) is a slowly debilitating neurodegenerative chronic illness that may progress for a decade or longer before death ensues. The disease often strikes later in life. This is evidenced by the fact that half of those over the age of 80 years are afflicted with the disorder. At present, it is the fourth leading cause of adult deaths in the US alone, at an annual cost of approximately $100 billion. As the longevity of the world""s population increases, this disease will become an even greater problem unless a better understanding of the disease process and its management is achieved.
Alois Alzheimer is credited with being the first to diagnose what is now known as Alzheimer""s disease (AD). In 1906, Alzheimer reported a case of what he termed xe2x80x9cpresenile dementiaxe2x80x9d in a 51 year old patient at a psychiatric meeting in Southwest Germany. He recognized certain characteristics that he felt differentiated it from the usual diagnosis of dementia. First was the early onset of the disease in an otherwise healthy young woman. More importantly, however, were the histological changes he found in sections of brain tissue from the patient. Alzheimer described seeing amyloid (starch-like) plaques and coarse-fibered proliferations of neurofibrils under the microscope. Several other researchers in years following reported similar findings of presenile dementia, and in 1910 a textbook of psychiatric disorders defined this form of dementia as xe2x80x9cAlzheimer""s disease.xe2x80x9d The eponym was adopted in the literature and became the standard. It is perhaps fitting since Alzheimer""s original observations are still the main criteria of diagnosis for the disease.
The plaques and neurofibrils described by Alzheimer, which are today called senile plaques and neurofibrillary tangles (NFT), are used as a definitive diagnosis of AD. The plaques and tangles are seen primarily in the hippocampus, amygdala, and the cerebral cortex. Evidence for either a molecular or immunological disease origin may be found in the plaques and tangles, depending upon a researcher""s point of reference. From a molecular perspective, the initial identification of specific mutations within the amyloid precursor protein (APP) and the presence of Axcex2 (a derivative of APP) in plaques points to a unique protein cause for AD. Also, several other protein players have since entered the AD arena.
These include the already mentioned major constituent of NFTs, tau, as well as three recent additions. Presenilins 1 and 2 are integral membrane proteins coded for on different chromosomes, that when mutated are responsible for up to 90% of the cases of autosomal dominant early-onset familial Alzheimer""s disease (FAD). Although FAD accounts for an only 10%, of all cases of AD, there is evidence of in interaction between the presenilins and APP. Therefore, even normal forms of the proteins may play a role in the far more common sporadic AD. Finally, a specific isoform of apolipoprotein E (apoE), apoE4, has been shown to be a strong genetic risk factor for AD. People carrying two copies of the of the E4 isoform have a statistically greater risk of developing late-onset and in vitro experiments have shown that apoE is capable of binding to Axcex2.
The histopathological investigations into AD also point to the immune response having an important role in disease progression. The presence of activated microglia, reactive astrocytes, acute phase proteins, and complement factors within and around neuritic plaques are all signs of in inflammatory response. It is known that AP is of binding specifically to C1q, which can trigger activation of the classical pathway of the complement cascade in an antibody-independent manner. Deposition of complexes and formation of immunomodulators by the cascade have been credited with activating the microgliaxe2x80x94macrophages of the brainxe2x80x94which in turn cause a progression and maintenance of the inflammation. Local tissue destruction follows, along with a further persistence ind increase in inflammation. The important unresolved question in this model is whether Axcex2 deposition and plaque formation or activation of complement and inflammation come first.
Prior Modes of Treatment of Alzheimer""s Disease
A major approach to the treatment of AD has involved attempts to augment the cholinergic function of the brain. An early approach was the use of precursors of acetylcholine synthesis, such as choline chloride and phosphatidyl choline (lecithin). Although these supplements are generally well tolerated, randomized trials have failed to demonstrate any clinically significant efficacy. Direct intracerebroventricular injection of cholinergic agonists such as bethanacol appears to have some beneficial effects, although this requires surgical implantation of a reservoir connecting to the subarachnoid space and is too cumbersome and intrusive for practical use. A somewhat more successful strategy has been the use of inhibitors of acetylcholinesterase (AChE), the catabolic enzyme for acetylcholine. Physostigmine, a rapidly acting, reversible AChE inhibitor, produces improved responses in animal models of learning, and in patients with AD some studies have demonstrated mild transitory improvement in memory following physostigmine treatment. The use of physostigmine has been limited because of its short half-life and tendency to produce symptoms of systemic cholinergic excess at therapeutic doses.
Recently, the acridine derivative tacrine (COGNEX(copyright);1,2,3,4-tetrahydro-9-aminoacridine) has been approved by the United States Food and Drug Administration for the treatment of dementia in AD. Tacrine was first synthesized nearly fifty years ago, and the pharmacology of this agent has been the subject of numerous studies. It is a potent centrally acting inhibitor of AChE. The side effects of tacrine may be significant and dose-limiting: abdominal cramping, nausea, vomiting, and diarrhea are observed in up to one-third of patients receiving therapeutic doses. Tacrine may also cause hepatotoxicity, as evidenced by the elevation of serum transaminases observed in up to 20% of patients treated. Because of the relatively small improvements that result from tacrine treatment and the significant side-effect profile, its clinical usefulness is limited.
Alzheimer""s disease and stroke are among the most difficult conditions to treat because it is essential to deliver therapeutically effective quantities of required drugs to the brain. Recently, folic acid has been found to be useful in the treatment of these conditions.
Recent research has indicated that folic acid supplements substantially reduce the incidence of Alzheimer""s disease and stroke in healthy aging subjects. Folate is necessary for DNA synthesis and repair. Sufficient amounts of folate are not readily available from food, and very small quantities of ingested folate ever reach the brain. Synthetic folic acid is more orally bioavailable than natural folate, but even synthetic folate may not be efficiently transported across the blood-brain barrier to be effective in the treatment of Alzheimer""s disease and stroke. A more reliable dosage form and route of administration is needed to ensure that sufficient quantities of this vitamin are delivered to the brain.
Stroke
The brain is highly vulnerable to disturbance of the blood supply; anoxia and ischemia lasting only seconds (called xe2x80x9cTransient Ischemic Attackxe2x80x9d or xe2x80x9cTIAxe2x80x9d) can cause neurological symptoms and within minutes can cause irreversible neuronal damage.
Blood flow to the central nervous system must efficiently deliver oxygen, glucose, and other nutrients and remove carbon dioxide, lactic acid, and other metabolic products. The cerebral vasculature has unique anatomical and physiological features that serve to protect the brain from circulatory compromise. When these protective mechanisms fail the result is a stroke. Broadly defined, the term stroke, or cerebrovascular accident, refers to the neurological symptoms and signs, usually focal and acute, that result from diseases involving blood vessels.
Prior Modes of Treatment of Stroke
When a TIA has been diagnosed, the goal of therapy is to prevent a stroke. If infarction has occurred, the most important objective of therapy is to prevent worsening of the stroke.
ANTICOAGULANT THERAPY. Heparin prevents clot propagation and formation by potentiating antithrombin IIII activity. The heparin-antithrombin III complex inactivates thrombin and other coagulation enzymes including factors X, XII, XI, and IX. Heparin also inhibits proliferation of vascular smooth muscle and platelet activation. Heparin therapy is sometimes advocated when a tightly stenotic internal carotid artery or an impending or completed carotid or middle cerebral artery occlusion is suspected. When a major carotid territory stroke is suspected, the middle cerebral artery stem (lenticulostriate) and peripheral (cortical surface) territory may both be infarcted. In this setting, acute anticoagulation is usually avoided because preventing further stroke is not an issue and hemorrhage into infarction in the lenticulostriate territory is a possible complication. Generally, heparin is given as a continuous intravenous infusion to raise the partial thromboplastin time to 1.5 to 2.5 times control. A 1000- to 10,000-unit bolus may be given prior to initiating the continuous infusion.
Sodium warfarin (Coumadin) inhibits the activation of vitamin-K, the essential cofactor in the activation of the vitamin K-dependent coagulation proteins. Chronic oral anticoagulation with sodium warfarin is considered in patients when an embolic or low-flow TIA or stroke is related to carotid siphon or middle cerebral stem stenosis. It is also considered for a 6-month trial to prevent subsequent embolism when the internal carotid artery is known to have been occluded recently. It is well established that the risk of hemorrhage is directly related to the intensity of anticoagulation. Therefore, low-intensity warfarin anticoagulation (prothrombin time ration 1.2 to 1.5 times control or international normalized ratio 1.5 to 2.7 or 2 to 3) is usually used. When the standard medical contraindications are present, antiplatelet therapy becomes the only option.
ANTIPLATELET THERAPY. Studies of the effect of antiplatelet agents on the natural history of TIAs and minor stroke all suffer from a lack of precise understanding of the pathophysiologic condition underlying the ischemic event. Aspirin has been the most widely studied antiplatelet agent. Paradoxically, aspirin has dual effects: it inhibits platelet formation of thromboxane A2, a platelet-aggregating, vasoconstricting prostaglandin, but it also inhibits the formation of prostacyclin, an antiaggregating, vasodilating prostaglandin derived from endothelial cells. Aspirin in low doses predominantly inhibits the production of thromboxane A2; therefore, many physicians recommend aspirin in doses of 300 mg or less per day.
Dipyridamole acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic adenosine monophosphate (AMP). The resulting elevation in cyclic AMP inhibits the aggregation of platelets. Ticlopidine is thought to inhibit platelet binding to fibrinogen, and recent studies have shown it to be comparable to aspirin in preventing stroke in patients with TIAs or stroke. Ticlopidine has the disadvantage of incurring a small risk of leukopenia, diarrhea, and rash. It is recommended for use as an antiplatelet agent only if aspirin is contraindicated or fails.
OTHER THERAPIES. Other pharmacological therapies useful in reducing stroke size include the administration of calcium channel antagonists (e.g., bepridil; calciseptine; cyproheptadine; diltiazem; flunarizine; fluspirilen; HA-1077; loperamide; nicardipine; nifedipine; niguldipine; nimodipine; nitrendipine; pimozide; ryanodine; verapamil), and administration of glutamate receptor antagonists (specifically the NMDA subtype) (e.g., AP3, (xc2x1)-; AP4, (xc2x1)-; AP5, (xc2x1)-; AP5, D(xe2x88x92)-; AP7, (xc2x1)-; AP7, D(xe2x88x92)-; CGS 19755; 7-chlorokynurenic acid; CPP, (xc2x1)-; CPP,D-; dextromethorphan; dextrorphan; 5,7-dichlorokynurenic acid; 6,7-dichlorquinoxaline-2,3-dione (DCQX); 5,5-dimethyl-1-pyrroline-N-oxide; 5-fluroindole-2-carboxylic acid; HA-966, (xc2x1)-; HA-966, R(+)-; HA-966, S(xe2x88x92)-; ketamine; kynurenic acid; MDL 105,519; memantine; MK-801; 1-napthyl-acetyl spermine; pentamidine isethionate).
A major object of the present invention is to provide a method for safely and conveniently administering folic acid to a patient in need of prevention or treatment of stroke or Alzheimer""s disease, in order to produce a rapid and reliable response. The method comprises the intranasal administration of an effective amount of folic acid to a patient suffering from, or at risk for, stroke or Alzheimer""s disease.
The objective of the present invention is to improve the rate of delivery of folic acid to the central nervous system by administering folic acid via the nasal route in order to speed the onset of effect and reduce the dose required for its beneficial effect. Intranasal delivery will improve drug bioavailability by direct absorption into the central nervous system, thereby avoiding extensive first-pass metabolism which may significantly lower the plasma concentrations of folic acid when it is administered via another route. As a result, small doses of folic acid, or derivatives thereof, can be administered which will result in fewer side effects, and the drug will be more tolerable and more effective in patients suffering from stroke or Alzheimer""s disease. Importantly, since folic acid is rapidly effective following intranasal administration, establishment of an ideal dose for a particular patient is greatly facilitated.
Intranasal dosage forms containing folic acid in combination with other drugs used in the treatment of stroke and/or Alzheimer""s disease may also be employed in the practice of the present invention.
With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention is further explained in the following detailed description of the preferred embodiments of the invention and in the appended claims.